JPWO2005018607A1 - Pharmaceutical formulations with improved solubility - Google Patents

Abstract

After dissolving a poorly soluble drug having the ability to form micelles in water to form micelles, the solubility was improved, including fixing the micelle structure formed with a poorly soluble drug with a compound that fixes the micelle structure. A method for producing a pharmaceutical preparation. This manufacturing method preferably further includes a step of returning the pH to neutral and / or room temperature after fixing the micelle structure. In addition, the poorly soluble drug targeted by this method forms micelles in water only in the presence of an acid or alkali and / or when heated. According to this production method, it is possible to produce a pharmaceutical preparation with improved solubility that can achieve improved oral absorption of poorly soluble drugs.

Description

The present invention relates to a preparation technique such as solubilization or rapid release of a poorly soluble drug, and a solubilized or rapid release pharmaceutical preparation.
In recent years, compounds found in drug development are often poorly soluble drugs that are difficult to dissolve in water. In the development of oral preparations, when poorly soluble drugs are administered orally, problems such as a decrease in oral absorption due to low solubility and variations are regarded as problems.
In order to solve this problem, various studies have been conducted on pharmaceutical preparation methods. For example, (1) a method in which a poorly soluble drug and a water-soluble polymer are dissolved in an organic solvent and the organic solvent is removed to obtain a solid dispersion (for example, Patent Document 1 and Non-Patent Document 1), (2) Difficult A method of pulverizing soluble drug particles to improve the dissolution rate (for example, Patent Document 2), (3) a method of solubilizing using a surfactant (for example, Patent Document 3), and the like have been reported.
However, since the method (1) uses a large amount of an organic solvent, the influence on the environment becomes a problem in production. It is also difficult to completely remove the solvent. The method (2) is known to require a very long processing time, and has a problem in production cost. Regarding the solubilization method of (3), no technique has been reported so far for efficiently solubilizing a poorly soluble drug.

WO 02/34254 WO 00/57881 WO97 / 41894 “Design and Evaluation of Orally Administered Drugs”, Mitsuru Hashida, Yakuho Hokpo, 1995, p178

An object of this invention is to provide the manufacturing method of the pharmaceutical formulation which improved the solubility which can achieve the oral absorption improvement of a poorly soluble drug.
Another object of the present invention is to provide a method for producing a pharmaceutical preparation with improved solubility capable of solubilizing or quickly releasing a poorly soluble drug.
Another object of the present invention is to provide a pharmaceutical preparation with improved solubility that can achieve improved oral absorption of poorly soluble drugs.

In the case of a poorly soluble drug, for example, a poorly soluble drug that forms micelles (molecular aggregate) in water only in the presence of an acid or alkali and / or when heated, the molecular aggregate is formed only by the drug molecule. When a surfactant or the like is added to the solution, the molecular assembly structure is fixed, and a solubilized solution can be obtained even when the pH is returned to neutral or room temperature. This was based on the knowledge that the oral absorbability was improved, and that the effect of improving the oral absorbability was maintained even when the solubilized solution was solidified.
That is, the present invention includes fixing a micelle structure formed of a poorly soluble drug with a compound that fixes the micelle structure after dissolving the poorly soluble drug having the ability to form micelles in water to form a micelle. A method for producing a pharmaceutical preparation with improved solubility is provided.
The present invention also provides a pharmaceutical preparation produced by the above production method.
The present invention also provides a pharmaceutical composition comprising a pharmaceutical preparation in which the micelle structure of a poorly soluble drug is fixed by a compound that fixes the micelle structure.

  Examples of the poorly soluble drug to be used in the present invention are, for example, hardly soluble in water (for example, solubility in water of 1000 g at 25 ° C. is 1 g or less), acid (preferably strong acid) or alkali (preferably strong alkali), And it will not be specifically limited if it forms a micelle (molecular assembly) in water and forms a clear solution only when heated. Examples of such agents include compounds having at least one dissociating group in the molecule and, if necessary, a hydrophobic group.

  Specific examples of such drugs include compounds having the following structural formula (4- (5H-dibenzo [a, d] cyclohepten-5-ylidene) -1- [3- [4-sulfamoylphenyl] -2 (E) -propenyl ] -Piperidine, monohydro-chloride) (hereinafter referred to as “AP-1067”) and 5-(((S) -2,2-dimethyl-cyclopropanecarbonyl) amino) -2- (4-(((S) -2, 2-dimethylcyclopropanecarbonyl) amino) phenoxy) pyridine (hereinafter referred to as “APC0576”) (Takehana et al., Biochem. Biophys. Res. Commun. 293 (20). 2) 945-952), and the like. Further, compounds having a cyproheptadine skeleton, such as cyproheptadine, and other skeleton compounds such as glycyrrhizic acid, tocopherol succinate, hydrocortisone succinate, prednisolone succinate, perphenazine, dantrolenato, tinidazole, dehydrocol Acid, lidocaine, tolazamide, trepibutone, naproxen, miconazole, tocopherol nicotinate, haloperidol, proglumide, probenecid, fen blueberry phen, pranoprofen, flurbiprofen, nateglinide, chemical formula 3 described in JP-A-11-116502 And compounds represented by Chemical formula 2, Chemical formula 5, Chemical formula 6, Chemical formula 7, Chemical formula 8, and Chemical formula 9 described in JP-A-7-109218.

AP-1067

In the present invention, examples of the compound that fixes the micelle structure include surfactants and water-soluble polymers.
Examples of the surfactant include one or a mixture of two or more of an anionic surfactant, a cationic surfactant, and a nonionic surfactant.
Examples of the anionic surfactant include sodium lauryl sulfate and dicetyl phosphate, but are not particularly limited as long as they are pharmaceutically acceptable.
Examples of the cationic surfactant include cetylpyridinium chloride, but are not particularly limited as long as they are pharmaceutically acceptable.
Examples of nonionic surfactants include polyoxyethylene type nonionic surfactants having polyoxyethylene in the hydrophilic group, and specific examples include polysorbates, polyoxyethylene hydrogenated castor oil, and polyoxyl 40 stearate. It is done. Sucrose fatty acid esters can be used as other nonionic surfactants, but are not particularly limited as long as they are pharmaceutically acceptable.

Examples of the water-soluble polymer include one or a mixture of two or more of polysaccharide derivatives, polyacrylic acid derivatives, polyoxyethylene, polyvinylpyrrolidone derivatives, polyvinyl alcohol, cyclodextrins and the like.
Examples of the polysaccharide include cellulose derivatives, particularly methylcellulose, hydroxypropylmethylcellulose, hydroxypropylcellulose and the like, but are not particularly limited as long as they are pharmaceutically acceptable.
Examples of the polyvinylpyrrolidone derivative include polyvinylpyrrolidone and 1-vinyl-2-pyrrolidone / vinyl acetate copolymer, but are not particularly limited as long as they are pharmaceutically acceptable.
Examples of cyclodextrins include α-cyclodextrin, β-cyclodextrin, γ-cyclodextrin, hydroxypropyl-β-cyclodextrin, and sulfobutyl ether-β-cyclodextrin.

In the present invention, first, a poorly soluble drug having the ability to form micelles is dissolved in water containing an acid or an alkali to form micelles. Here, the acid is preferably a strong acid (preferably an inorganic acid) such as hydrochloric acid, sulfuric acid, or phosphoric acid. Alternatively, the alkali is preferably a strong alkali (preferably an inorganic alkali compound) such as sodium hydroxide or potassium hydroxide. Here, the aqueous solution containing an acid preferably has a pH of 3 or less, and the aqueous solution containing an alkali preferably has a pH of 9 or more. In any case, it is preferable that the poorly soluble drug has a pH suitable for forming micelles in water.
Here, the acidic aqueous solution or alkaline aqueous solution is further heated to preferably 35 to 100 ° C., more preferably 40 to 60 ° C., and the poorly soluble drug is dissolved therein to form micelles in water. However, it can also be performed at room temperature without heating.
Furthermore, without adding an acid or an alkali, water can be heated to the above temperature, and a poorly soluble drug can be dissolved therein to form micelles in water.
Thus, after a poorly soluble drug is dissolved in water to form a micelle, in the present invention, the micelle structure formed of the poorly soluble drug is fixed by a compound that fixes the micelle structure.

Fixing a micelle structure in the present invention means a hardly soluble drug, for example, as described above, in the presence of an acid or alkali, and / or a poorly soluble drug that forms micelles in water only when heated, in the presence of an acid or alkali. And / or heating to form micelles to form a clear solution, and by adding a compound to this, the micelle structure once formed is stabilized, so that the pH becomes neutral, or the temperature is brought to room temperature. It means that the micelle structure is maintained even if it is returned.
As described above, it is considered that the poorly soluble drug is dissolved as follows. That is, for example, in a poorly soluble drug having a micelle structure formed by raising the temperature or in the presence of an alkali, it is considered that the dissociated group is dissociated and the hydrophobic group is assembled (FIG. 1). When the pH of this liquid is returned to neutral, the dissociation degree of the dissociating groups is suppressed, and the repulsion between the dissociating groups is suppressed, and the hydrophobic groups are exposed to contact with water, resulting in precipitation. On the other hand, when a compound that immobilizes micelles such as a surfactant is added once the micelles are formed, the hydrophobic portion of the surfactant enters the gaps (hydrophobic portions) of the micelles formed by the poorly soluble drug (Fig. 2) The micelle structure is stabilized, and even when the pH is neutral and the temperature is returned to room temperature, it is possible to keep the micelle structure maintained.

The order of addition in immobilizing micelles is, for example, by dissolving a poorly soluble drug in water to form micelles, and then adding a compound that fixes the micelle structure to form a micelle structure formed with a poorly soluble drug. Either a fixing method or a method in which a poorly soluble drug is dissolved in water in the presence of a compound that fixes the micelle structure to form a micelle and the micelle structure formed with the poorly soluble drug is fixed.
Even if the micelle structure of the poorly soluble drug is stable in water and the pH is neutral or the temperature is room temperature, the compound can be used in any amount as long as the micelle structure does not break. be able to. For example, the compound that fixes the micelle structure may be used in an amount of 0.01 mg to 20 g per 1 g of poorly soluble drug.

In the present invention, after fixing the micelle structure formed with the poorly soluble drug in this way, it can be used as it is, but when the solution becomes acidic or alkaline by the addition of acid or alkali, It is preferable to add an alkali or an acid to make it neutral. If heated, it is preferably cooled to room temperature.
In the present invention, the pharmaceutical preparation prepared in this way can be used as it is, but it can also be prepared in a solid form by removing water by a conventional method. The step of preparing such a solid can be performed by a wet granulation method, for example, a fluidized bed granulation method, a high-speed stirring granulation method, a spray drying method, or a freeze drying method. Here, for example, as the wet granulation method, a liquid pharmaceutical preparation is granulated on a pharmaceutically acceptable granular material or powdery material such as an inert diluent, a swelling agent or a sweetening agent, which will be described later, and granulated. Can be mentioned.

In the pharmaceutical composition of the present invention, in addition to the above pharmaceutical preparations, known auxiliary substances, for example, excipients such as lactose, sucrose, corn starch, binders such as hydroxypropylcellulose, hydroxypropylmethylcellulose, macrogol, Disintegrants such as low-substituted hydroxypropyl cellulose, crystalline cellulose, croscarmellose sodium, carboxymethyl starch, sweeteners such as saccharin, aspartame, acesulfame K, lubricants such as magnesium stearate and talc, alginic acid, lauryl sulfate Surfactants such as sodium and polysorbate 80 can be included.
Examples of the dosage form of such a pharmaceutical composition include tablets, powders, pills, granules, capsules, solutions, dragees, and syrups.
EXAMPLES Next, an Example demonstrates this invention in detail.

Reference Example 1 Confirmation of micelle (molecular assembly) formation AP-1067 (4- (5H-dibenzo [a, d] cyclohepten-5-ylidene) -1- [3- [4-sulfamoylphenyl] -2 at various concentrations An alkaline aqueous solution (pH = 13) of (E) -propenyl] -piperidine, monohydro-chloride) was prepared, and the surface tension thereof was measured. As a result, it can be seen that as the concentration of AP-1067 increases, the surface tension decreases and becomes constant above a certain concentration. That is, it was considered that AP-1067 has a critical micelle concentration in an alkaline aqueous solution and forms a molecular assembly (micelle).

Example 1 Solubilization of AP-1067 About 10 mg of AP-1067 was dispersed in 1 mL of water, and an aqueous sodium hydroxide solution was added to make pH = 13 or higher. When this suspension was heated to 45 ° C., a clear AP-1067 alkaline aqueous solution in which micelles of AP-1067 were formed was obtained (AP-1067 concentration: about 10 mg / mL).
The micelle formed by adding 40 mg of sodium lauryl sulfate (SDS) to this alkaline aqueous solution was fixed. Thereafter, an aqueous hydrochloric acid solution was added dropwise to adjust the pH to neutral, thereby obtaining a clear AP-1067 neutral solubilized solution in which the micelles of AP-1067 were fixed. The concentration of AP-1067 at this time was 9.1 mg / mL.
Since the solubility of AP-1067 in water at room temperature is about 0.03 mg / mL, the solubility was improved about 300 times by applying this solubilization method.

Reference Example 2 Confirmation of micelle (molecular assembly) shape fixation AP-1067 solubilized solution was prepared by the method of Example 1 above using heavy water, sodium deuteride and deuterated hydrochloric acid, and NMR (NOESY) measurement of this aqueous solution was performed. Went.
From the obtained data, a cross peak was observed between the methylene proton at the central part of the long alkyl chain of SDS and the proton at the tricyclic part of AP-1067, and both protons were present in the vicinity. confirmed. Furthermore, when the pH of the solution is neutral, cross peaks are observed between the methylene proton and terminal methyl proton in the central part of the long alkyl chain of SDS and the proton in the tricyclic part of AP-1067. It was confirmed that protons exist nearby. From this, it was considered that AP-1067 and SDS as the surfactant exist in the solution in the fixed micelle form shown in FIG.

Example 2 Solubilization of AP-1067 About 10 mg of AP-1067 was dispersed in 1 mL of water, and an aqueous sodium hydroxide solution was added to adjust the pH to 13 or higher. When this suspension was heated to 45 ° C., a clear AP-1067 alkaline aqueous solution in which micelles of AP-1067 were formed was obtained (AP-1067 concentration: about 10 mg / mL).
The micelle formed by adding 100 mg of polysorbate 80 to this alkaline aqueous solution was fixed. Thereafter, an aqueous hydrochloric acid solution was added dropwise to adjust the pH to neutral to obtain a clear AP-1067 neutral solubilized solution in which the micelles of AP-1067 were fixed. The concentration of AP-1067 at this time was 10.3 mg / mL.
Since the solubility of AP-1067 in water at room temperature is about 0.03 mg / mL, the solubility was improved about 300 times by applying this solubilization method.

Comparative Example 1
AP-1067 10 mg and SDS 40 mg were dispersed in 1 mL of water, and this suspension was heated to 45 ° C. and sonicated for 1 hour 30 minutes, but a clear AP-1067 solubilized solution could not be obtained. It was.
Comparative Example 2
10 mg of AP-1067 and 100 mg of polysorbate 80 were dispersed in 1 mL of water, and this suspension was heated to 45 ° C. and sonicated for 1 hour and 30 minutes, but it was possible to obtain a clear AP-1067 solubilized solution. could not.

Example 3 Solubilization of APC0576 APC0576 10 mg and cetylpyridinium chloride monohydrate 83 mg were dispersed and dissolved in 1 mL of 1.5 mol / L hydrochloric acid aqueous solution, and this suspension was heated to 50 ° C. and sonicated. A clear APC0576 acidic aqueous solution was obtained in which micelles of the poorly soluble drug APC0576 were fixed (APC0576 concentration: about 10 mg / mL).
A 10 mol / L aqueous sodium hydroxide solution was added dropwise to this acidic aqueous solution to adjust the pH to near neutral, and a clear APC0576 solubilized solution of about 7 mg / mL was obtained in which APC0576 micelles were fixed (see FIG. 3).
Since the solubility of APC0576 in water at room temperature is about 0.0016 mg / mL, the solubility was improved about 4400 times by applying this solubilization method.
Comparative Example 3
APC0576 10 mg and cetylpyridinium chloride monohydrate 85 mg were dispersed in 1 mL of water, and this suspension was heated to 50 ° C. and sonicated for 1 hour 30 minutes. A clear APC0576 solubilized solution was obtained. (See Fig. 3).

Example 4 Preparation of AP-1067 solution into solid form (granule)
250 g of partially pregelatinized starch (Asahi Kasei, PCS) was charged into Fukae Kogyo High Speed Mixer Mini, and 338.9 g of AP-1067 solubilized solution obtained in the same manner as in Example 1 (AP-1067 concentration) : 29.5 mg / mL, sodium lauryl sulfate concentration: 118 mg / mL) was added dropwise to perform high-speed stirring granulation. The obtained granulated product was dried on a shelf and sieved to obtain a granular pharmaceutical preparation.

Example 5 Evaluation of dissolution of AP-1067 solubilized liquid and solubilized liquid adsorbent granules AP-1067 solubilized liquid obtained in Example 1 and granular pharmaceutical preparation obtained in Example 4 (solubilized in the figure) The dissolution property of the poorly soluble drug AP-1067 in the liquid adsorption granules) was evaluated by the paddle method (50 rpm, 0.1 w / v% polysorbate 80 aqueous solution: 900 mL, AP-1067: 10 mg / vessel). Here, the solubilized solution and the granular pharmaceutical preparation were evaluated with n = 3, and the others were evaluated with n = 1.
A result is shown in FIG. 4, and it turns out that the elution property of AP-1067 in the AP-1067 solubilized solution and the granular pharmaceutical preparation of the present invention is greatly improved as compared with the AP-1067 powder.

Example 6 Evaluation of Large Oral Absorption Plasma concentration transition (Fast Administration, AP-1067: 3 mg / kg, n = 3, mean ± SE) when AP-1067 preparation was orally administered to beagle dogs was The solubilized AP-1067 obtained in the above and the granular pharmaceutical preparation obtained in Example 4 (the solubilized granules adsorbed in the figure) were examined.
The results are shown in FIG. 5 and Table 1. It can be seen that the solubilization of AP-1067 according to the present invention significantly improves AUC and Cmax compared to AP-1067 drug substance powder-filled capsule. It can also be seen that even if this solubilized solution is made into a solid preparation, the effect is hardly changed.

本発明によれば、難溶性薬物の溶解性が向上し経口吸収性が改善された医薬品製剤、及びその効率的な製造方法が提供される。

ADVANTAGE OF THE INVENTION According to this invention, the pharmaceutical formulation which the solubility of the hardly soluble drug improved and oral absorption was improved, and its efficient manufacturing method are provided.

It is the figure which showed the state in which a poorly soluble medicine forms the micelle. It is the figure which showed the state which added the compound which fixes a micelle structure to the hardly soluble drug which formed the micelle, and fixed the micelle of the hardly soluble drug. 2 is a photograph showing the state of a liquid of a hardly soluble drug APC0576 solubilized solution prepared in Example 3 and a hardly soluble drug APC0576 suspension prepared in Comparative Example 3. FIG. The elution property of the poorly soluble drug AP-1067 in the AP-1067 solubilized solution and granular pharmaceutical preparation of the present invention is shown. The plasma concentration transition of AP-1067 when the AP-1067 solubilized solution and granular pharmaceutical preparation of the present invention are orally administered to beagle dogs is shown.

Claims (15)

After dissolving a poorly soluble drug having the ability to form micelles in water to form micelles, the solubility was improved, including fixing the micelle structure formed with a poorly soluble drug with a compound that fixes the micelle structure. A method for producing a pharmaceutical preparation. The process according to claim 1, wherein the poorly soluble drug forms micelles in water only in the presence of an acid or alkali and / or when heated. The method according to claim 1 or 2, wherein after the micelle structure is fixed, the pH is further returned to neutral and / or room temperature. The method according to any one of claims 1 to 3, wherein the compound that fixes the micelle structure is a surfactant and / or a water-soluble polymer. The surfactant and / or the water-soluble polymer is at least one compound selected from anionic surfactants, cationic surfactants, nonionic surfactants, polysaccharides, polyacrylic acids, polyethers and cyclodextrins. The manufacturing method according to claim 4. The production method according to claim 4, wherein the surfactant is a polyoxyethylene nonionic surfactant. Surfactant and / or water-soluble polymer is sodium lauryl sulfate, cetylpyridinium chloride, polysorbate 80, α-cyclodextrin, β-cyclodextrin, γ-cyclodextrin, hydroxypropyl-β-cyclodextrin and sulfobutyl ether-β The production method according to claim 4, which is at least one compound selected from cyclodextrin. The production method according to any one of claims 1 to 7, wherein a poorly soluble drug is dissolved in an acidic or alkaline aqueous solution to form micelles. The production method according to any one of claims 1 to 7, wherein a poorly soluble drug is dissolved in a heated acidic or alkaline aqueous solution to form micelles. The manufacturing method according to any one of claims 1 to 9, wherein the micelle structure formed of the poorly soluble drug is fixed and then prepared in a solid form. The manufacturing method according to claim 10, wherein the step of preparing the solid is performed by a wet granulation method. The manufacturing method according to claim 10, wherein the step of preparing the solid is performed by a fluidized bed granulation method, a high-speed stirring granulation method, a spray drying method or a freeze drying method. The pharmaceutical formulation manufactured by the method of any one of Claims 1-12. A pharmaceutical composition comprising a pharmaceutical preparation in which a micelle structure of a poorly soluble drug is fixed by a compound fixing the micelle structure. The pharmaceutical composition containing the pharmaceutical formulation manufactured by the method of any one of Claims 1-12.

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